Sickle cell disease is an autosomal recessive disorder and the most common genetic disease affecting African-Americans. Approximately 0.15% of African-Americans are homozygous for sickle cell disease, and 8% have sickle cell trait. Hemoglobin S polymerization leads to red cell rigidity, microvascular obstruction, inflammation, and end-organ ischemic injury. Our published data indicate that up to 50% of sickle cell patients have vascular dysfunction due to impaired bioavailability of endogenous nitric oxide, due in large part to scavenging of nitric oxide by cell-free hemoglobin. We recently have completed studies that directly demonstrate endothelial dysfunction in patients with sickle cell disease, characterized by decreased ACh dependent vasorelaxation in forearm blood flow studies, distinct from the nitric oxide resistance above. Further, we have found in sickle cell patients a new association between low levels of apoA-I, pulmonary hypertension and endothelial dysfunction. Raising levels of HDL and therefore apoA-1, could have the effect of ameliorating the endothelial dysfunction characteristic of sickle cell disease by affecting endothelium dependent vasorelaxation. Therapies directed at restoring HDL in these patients may be beneficial. HDL is thought to promote vascular health in a variety of ways, some of which are unrelated to lipid transport. One of the best-known mechanisms relates to efflux of cholesterol from atherosclerotic plaque, yet HDL is thought to have several antithrombotic and anti-inflammatory effects. In vitro HDL attenuates formation of oxidized LDL and inhibits endothelial cell expression of inflammatory cell adhesion molecules. It is also thought to mediate NO production via stimulation of eNOS5, thereby modulating endothelial function. In a study of subjects with atherosclerosis, low HDL levels correlated with impaired vasomotor relaxation via brachial artery FMD. Another study utilizing recombinant HDL cholesterol infused into brachial arteries of hypercholesterolemic men resulted in increased acetylcholine mediated blood flow that was inhibited by the infusion of L-NAME, an eNOS inhibitor, suggesting that HDL increased blood flow via an eNOS dependent mechanism. This may have implications not only for subjects with atherosclerosis, but also for those with sickle cell disease and endothelial dysfunction. We propose that niacin therapy could improve vascular reactivity in response to acetylcholine. Several options for increasing HDL levels have been previously utilized in forearm flow studies using venous occlusion plethysmography or flow-mediated dilation. Reconstituted HDL (rHDL), apoA-1 mimetics and niacin therapy were all shown to improve endothelial dysfunction, and proved safe and effective. This trial will aim to 1) establish the effects of niacin treatment on raising HDL levels in subjects with sickle cell disease, 2) investigate whether niacin treatment would result in improvement of endothelial-dependent relaxation via venous occlusion plethysmography, and 3) compare the efficacy of peripheral arterial tonometry measurements to venous occlusion plethysmography and flow-mediated dilation as indicators of vascular dysfunction. Thirteen subjects with HbSS sickle cell disease have participated in this ongoing study. Subjects were recruited while in steady state and were not receiving chronic transfusions. Following an overnight fast, subjects underwent PAT. According to manufacturer specifications, RH-PAT indices &#8804; 1.67 are indicative of endothelial dysfunction and those > 1.67 represent normal endothelial function. The subjects subsequently underwent venous occlusion plethysmography (AI6, D.E. Hokanson, Inc). Infusions of acetylcholine (ACh) and sodium nitroprusside (SNP) were administered to measure endothelium-dependent and endothelium-independent blood flow, respectively. To further characterize the nitric oxide resistance state, plasma samples from the first eight patients were assayed for NO consumption, and nitrite, a NO metabolite. Following intra-arterial infusion of 7.5, 15, and 30 g/min of ACh, patients with an RH-PAT index &#8804; 1.67 had an increase in blood flow over baseline of 196 30%, 287 43%, and 338 53%, respectively. This was not significantly different from the percentage change in blood flow response in patients with RH-PAT index > 1.67 (281 68%, 277 48%, 407 53%, respectively, p = 0.60). In contrast, patients with an RH-PAT index &#8804; 1.67 demonstrated a significantly blunted response to 0.8, 1.6, and 3.2 g/min infusions of SNP (28 7%, 45 11%, and 76 17% vs. 85 18%, 142 36%, and 240 48%, respectively, p < 0.001). This blunted response was also observed when comparing absolute forearm flow values (p < 0.01). LLactate dehydrogenase, an established biomarker of the NO resistance state and associated endothelial dysfunction in sickle cell disease, was found to be inversely correlated with plasma nitrite levels (Spearman r = -0.95, p = 0.001). Plasma nitrite levels were also inversely correlated with NO consumption (Pearson r = -0.80, 95% CI = -0.96 to -0.23, p = 0.016). Patients with an RH-PAT &#8804; 1.67 demonstrated greater NO consumption than patients with an RH-PAT > 1.67 (3.32 M 0.49, n = 4 vs. 2.06 M 0.18, n = 4, (mean SEM), p= 0.029), consistent with a state of decreased NO bioavailability. Plasma nitrite reserve in patients with sickle cell disease has not been clearly established, but these data suggest a potential relationship between decreased nitrite and NO resistance. Interestingly, decreased plasma nitrite levels have been shown to correlate with endothelial dysfunction in other patient populations. In this cohort of sickle cell subjects, RH-PAT was closely associated with the NO-mediated component of endothelial function. Lower RH-PAT is associated with blunted response to SNP and increased NO consumption, suggesting that RH-PAT provides a non-invasive method for assessing NO resistance in sickle cell disease. In addition, our results present preliminary support that plasma hemoglobin redirects NO metabolism away from nitrite production. The study was approved on July 24, 2007 and the first volunteer was enrolled on September 17, 2007. To date we have enrolled 21 subjects. Below is the status of the enrolled subjects: 12 subjects have completed the study 4 subjects are currently on study 2 subjects are being scheduled to start the study 1 subject completed the screening process and elected not to participate 1 subject was withdrawn due to a Serious Adverse Event 1 subject was found ineligible during the screening process.